DNA甲基化检测在绝经后女性子宫内膜癌筛查中的应用价值

方法 选取2020年5月至2021年10月就诊于北京协和医院妇产科、可疑内膜病变、拟行宫腔镜检查的绝经女性143例，术前收集宫颈脱落细胞进行基因甲基化检测。同时收集患者基本临床信息、生物标记物与经阴道超声（TVS）的子宫内膜厚度等。以宫腔镜下内膜组织病理学诊断为金标准，采用多因素logistic回归模型分析子宫内膜癌的相关因素，利用受试者工作特征（ROC）曲线下的面积（AUC）重点分析基因甲基化检测联合或不联合超声检查对绝经后妇女子宫内膜癌的筛查效能

结果 143例患者分为内膜癌组（56例）和对照组（87例），年龄分别为（59.27±6.45）和（61.07±8.26）岁（ P =0.051）。多因素分析发现，CA125≥35 U/ml、绝经出血、绝经内膜厚度≥5 mm、CDO1甲基化（ΔCt≤8.4）、CELF4甲基化（ΔCt≤8.8）是发生子宫内膜癌的相关因素， OR 值（95% CI ）分别为33.23（2.51~1 335.28）、8.41（1.81~39.05）、14.45（2.35~88.84）、17.34（3.34~89.98）、44.01（6.79~285.25），均 P <0.05。双基因甲基化（CDO1 ΔCt≤8.4或CELF4 ΔCt≤8.8）诊断内膜癌的灵敏度、特异度最高，分别为87.5%（95% CI ：75.9%~94.8%）和90.8%（95% CI ：82.7%~95.9%）。TVS联合DNA甲基化检测可进一步提高灵敏度，为100.0%（95% CI ：93.6%~100.0%），但不能改善特异度，为59.8%（95% CI ：48.8%~70.1%）

结论 对于绝经后女性宫颈细胞学DNA甲基化筛查内膜癌的准确性优于其他无创临床方案。联合TVS可以改善筛查的敏感性。 子宫内膜癌;癌症早筛;DNA甲基化;经阴道超声;异常子宫出血 ABSTRACT Objective To explore the application value of cervical exfoliated cell DNA methylation (CDO1 m and CELF4 m) combined with or without transvaginal sonography (TVS) for screening endometrial cancer in postmenopausal women

Methods A total of 143 postmenopausal women who underwent hysteroscopy for suspected endometrial lesions in the Department of Obstetrics and Gynecology of Peking Union Medical College Hospital from May 2020 to October 2021 were enrolled in this study. The cervical exfoliated cells were collected for gene methylation before hysteroscopy. Clinical information, tumor biomarkers, and endometrial thickness of TVS were also collected. With endometrial histopathology as the gold standard, multivariate unconditional logistic regression was applied to analyze the risk factors of endometrial cancer. The role of gene methylation with or without TVS were specifically explored

Results The 143 patients were divided into an endometrial cancer group ( n =56) and a control group ( n =87), aged (59.27±6.45) and (61.07±8.26) years, respectively ( P =0.051). Multivariate logistic regression analysis showed that, CA125≥35 U/ml, postmenopausal bleeding, endometrial thickness≥5 mm, CDO1 m ΔCt≤8.4, and CELF4 m ΔCt≤8.8 were the risk factors for endometrial cancer, with OR (95% CI) of 33.23 (2.51-1 335.28), 8.41(1.81-39.05), 14.45 (2.35-88.84), 17.34 (3.34-89.98), and 44.01 (6.79-285.25), respectively (all P values < 0.05). The sensitivity and specificity of dual-gene methylation (CDO1 or CELF4) in the screening of endometrial carcinoma were both higher than others factors, reaching 87.5% (95% CI: 75.9%-94.8%) and 90.8% (95% CI: 82.7%-95.9%), respectively. TVS combined with DNA methylation detection further improved the sensitivity to 100.0% (95% CI: 93.6%-100.0%), but could not improve the specificity (59.8%, 95% CI: 48.8%-70.1%)

Conclusions In postmenopausal women with suspected endometrial lesions, the accuracy of cervical cytology DNA methylation is better than other noninvasive clinical indicators for the screening of endometrial cancer. DNA methylation combined with TVS can further improve the sensitivity of screening. Endometrial cancer;Early cancer screening;DNA methylation;Transvaginal sonography;Abnormal uterine bleeding Li Lei, Email: mocdef.3ab61hgielil Copyright by Chinese Medical Association No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission. All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified. 引用本文 孔令华,肖晓萍,万茹,等. DNA甲基化检测在绝经后女性子宫内膜癌筛查中的应用价值\[J\]. 中华医学杂志,2023,103(12)：907-912. DOI:10.3760/cma.j.cn112137-20220929-02058 子宫内膜癌是最常见的妇科恶性肿瘤，全球和我国每年新发分别达到41.74万和7.11万例，每年死亡病例9.7万和1.71万。早期识别高危患者及癌前病变、实现癌症早筛、有效检测癌症进展和治疗，是当前内膜癌诊疗领域的重大课题之一。对于绝经后出血、子宫内膜厚度超过4 mm的患者，仅有8%的患者存在内膜增生和内膜癌；反复绝经后出血的患者中内膜病变的比例仅提升到9%。内膜癌评估主要依赖于有创性操作，如诊断性刮宫、宫腔镜检查、宫腔细胞学和病理学微量检测等，但漏诊率较高。目前国内外都没有可用于临床实践的、无创性筛查方案推荐。 抑癌基因的表观遗传学沉默对于癌症发生和进展有重要作用。已有大量有关内膜癌发生发展的甲基化研究，最新研究表明通过宫颈脱落细胞的自采集可以改善内膜癌的早期诊断。研究者已经申请了多项宫颈细胞学甲基化检测用于内膜癌的临床试验，开发了相应的试剂盒（NCT03744962、NCT04651738、NCT05290922和NCT05290415）。基于这些工作，本研究在队列研究中，应用宫颈脱落细胞中CDO1基因甲基化（CDO1m）和CELF基因甲基化（CELF4m）检测对可疑内膜病变的绝经后女性进行筛查，并探索细胞学甲基化联合或不联合经阴道超声（transvaginal ultrasound，TVS）的准确性。